Adenovirus (Ad) E1A is presently in phase l/ll clinical trials for the treatment of human malignancy. In order to optimize this form of therapy, we must understand the molecular basis for the anti-tumorigenic effect of E1A. We established that: the capacity of E1A to elicit a vigorous NK cell and T cell anti-tumor immune response is an important component of the anti-tumorigenic activity of E1A. The expression of E1A, but not mutant forms of E1A unable to interact with the cellular transcriptional co-adaptor molecules p300 or CBP (abbreviated E1A-Ap300), increases the expression of NKG2D ligands on the surface of tumor cells. Consequently, tumor cells that express E1A are eliminated by NK cells in vivo in a NKG2D-dependent manner. The upregulation of NKG2D ligands contributes to the immune-mediated decrease in tumorigenicity mediated by E1 A. The present use of E1A in the treatment of human malignancy does not exploit the immune-mediated, anti-tumorigenic activity of E1A. Studies in this proposal will define the molecular basis for the immune-mediated, anti-tumorigenic activity of E1A. In the first aim of the proposal we will explore the molecular mechanism whereby the interaction of E1A with p300 or the highly related transcriptional coadaptor protein, CBP, increases the expression of NKG2D ligands on the surface of tumor cells. In the second aim we will determine if the upregulation of NKG2D ligands on tumor cells by E1A is sufficient to induce a CD8+, E1 A-specific T cell response or if other pro-immunogenic activities of E1A are involved. In third aim, we will ascertain if E1A can be used as a molecular adjuvant to elicit antigen-specific anti-tumor immune responses Aim 1: Determine the molecular mechanisms for the ability of E1A, but not E1A-Ap300, to increase the expression of NKG2D ligands. Aim 2: Determine the molecular basis for the robust, E1 A-specific, CD+8 T cell response elicited by tumor cells that express E1A. Aim 3: Determine if the pro-immunogenic activities of E1A can be harnessed to elicit vigorous tumor antigen-specific immune responses.